JP6413288B2 - Cell capture processing system having cell capture device and treatment liquid supply kit for incorporation of the cell capture processing system - Google Patents

Description

  The present invention is used to sort and concentrate cells having a predetermined size in a biological sample, in particular, circulating tumor cells (CTC) contained in blood by filtering. The present invention relates to a cell capture processing system having a cell capture device and a treatment liquid supply kit incorporated in the cell capture processing system.

  2. Description of the Related Art Conventionally, a cell analyzer for selecting and concentrating cells contained in a biological sample by filtration with a predetermined size and analyzing them with high accuracy is known. For example, as a method for early detection of metastatic malignant tumors, a method for detecting circulating tumor cells (CTC) has recently attracted attention. Compared with other methods, CTC detection is expected to be less invasive and accurately diagnose metastatic malignant tumors, and is likely to be used as an indicator of patient prognosis and therapeutic effects. It is because it has been. As one of the CTC detection methods, Patent Document 1 proposes a microfluidic device including a size selection microcavity array.

  CTC is a very rare cell contained in the blood of a metastatic cancer patient, and in order to perform accurate detection, an operation for selecting and concentrating CTC to a concentration suitable for detection is necessary as a pretreatment. . In Patent Document 1, as a feature of a microfluidic device having a size-selective microcavity array, (1) blood is lysed or leukocytes are removed when compared with other concentration methods using monoclonal antibodies. (2) Able to perform analysis from blood separation to staining and washing consistently, (3) The device itself is small and inexpensive, and (4) Micro It is described that, by optimizing the structure and arrangement of the cavity array, the collection efficiency by capturing the tumor cells can be increased.

  Further, as a cell analysis apparatus by filtration, not only those applied for the detection of the above-mentioned CTC, but also a cell analysis apparatus for separating at least one selected from red blood cells, white blood cells and bacteria has been proposed. (For example, refer to Patent Document 2). The cell analyzer described in Patent Document 2 includes a cell discriminating unit for enabling discrimination of cells of a predetermined size in a biological sample, cells passing through gaps between a plurality of plate-like units, and a plurality of plates A sample adjusting unit for adjusting the measurement sample using at least one of the cells captured by the shaped part.

JP 2011-163830 A JP 2010-85181 A

  Although the microfluidic device described in Patent Document 1 has a feature that it can perform consistently from separation of blood to staining and washing, processing such as staining and washing of cells from the viewpoint of capture efficiency and analysis accuracy. Therefore, the processing time inevitably tends to be long. Therefore, it is very difficult to shorten the analysis time (TAT: Turn Around Time) until all the operations of one sample are completed, and a method for efficiently processing a plurality of samples is strongly demanded. In order to solve this technical problem, a method of providing a plurality of cell trapping devices for filtration and moving them in parallel can be considered. In that case, since it is necessary to provide a plurality of sets of processing liquids used for processing such as staining and washing of cells according to the number of cell trapping devices, the number of supply tanks (supply tanks) for supplying the processing liquid is reduced. A multiple increase is inevitable. In addition, the treatment liquid must be exchanged for each cell trapping device, and the exchange frequency increases and the exchange time takes longer.

  Further, the cell analyzer described in Patent Document 2 has the same problem as described above. This cell analyzer is provided with a plurality of cleaning liquid supply units, replacement liquid supply units, and waste liquid units for one of the cell discriminating units, and each includes a cleaning liquid tank, a replacement liquid tank, and a waste liquid tank. When the number of cell discriminating units is increased, the number of processing liquid tanks is increased. Each of these treatment liquid tanks has a structure in which each treatment liquid is supplied from a storage tank, but the number of each treatment liquid tank needs to be newly increased according to the number of cell discriminating units, so the installation space increases. In addition, the maintenance of the treatment liquid tank becomes complicated.

  Thus, in the prior art, in order to efficiently process a plurality of specimens, it is not recognized at all that a plurality of cell capture devices used for sorting and concentrating by filtration are used. In particular, specific proposals have been made for the handling method of each processing solution and the configuration of each processing solution supply tank that are used simultaneously when performing processing such as washing, replacement, and staining of a plurality of cell capture devices. It wasn't. Therefore, in response to technical problems associated with the use of multiple cell capture devices, that is, shortening the processing time, securing the installation space for each processing liquid supply tank (tank), simplifying maintenance, and reducing processing costs Was not enough.

  The present invention has been made in view of the above-described conventional problems, and is a cell capture device used for sorting and concentrating cells of a predetermined size in a biological sample by filtration. In addition to reducing the time required for various treatments, including washing, immobilization, permeation, staining, etc. A cell capture processing system that can process a plurality of specimens efficiently and at low cost by incorporating the whole cell capture processing system having the cell capture device and simplifying the maintenance, and the cell capture system are incorporated in the cell capture system. It is an object of the present invention to provide a processing liquid supply unit capable of performing the above.

  In the cell capture processing system that operates a plurality of cell capture devices at the same time, the present inventors provide various processing liquid supply tanks used when processing cells in the cell capture device between the plurality of cell capture devices. The present inventors have found that the above-mentioned problems can be solved by constructing a shared system and incorporating a treatment liquid supply kit having one of each treatment liquid supply tank into the cell capture treatment system.

That is, the configuration of the present invention is as follows.
[1] The present invention is a cell capture processing system having a cell capture device for sorting and concentrating cells of a predetermined size in a biological sample by filtration, and a plurality of the cell capture devices, The cells present in the biological sample are subjected to at least one treatment selected from the group consisting of a washing treatment, a substitution treatment, an immobilization treatment (preservation treatment), a permeation treatment, and a staining treatment. Each of the treatment liquid supply tanks each holding a treatment liquid, wherein the treatment liquid held in each of the treatment liquid supply tanks is shared among a plurality of the cell trapping devices, The present invention relates to a cell capture processing system.
[2] The present invention further includes only one waste liquid tank for storing a waste liquid, and the waste liquid tank is shared among a plurality of the cell trapping devices. The present invention relates to a cell capture processing system.
[3] In the present invention, the flow rate or flow velocity when supplying the treatment liquid from each one of the treatment liquid supply tanks to the plurality of cell capture devices is substantially the same among the plurality of cell capture devices. The length and diameter of the flow path for guiding and supplying the treatment liquid, the flow rate of the treatment liquid, and the positional relationship when arranging the treatment liquid supply tank and the plurality of cell trapping devices It is related with the cell capture processing system as described in said [1] or [2] characterized by adjusting at least any one of these.
[4] According to the present invention, different types of treatment liquids according to the content of the treatment may include n1 cell capture devices, and the number of specimens in the biological sample processed by one of the cell capture devices. [1] to [1], wherein when m samples are used, the processing liquid supply tank holds a volume amount of n (n = n1 × m) times or more of the volume required for one processing of the sample. [3] The cell capture processing system according to any one of [3].
[5] The present invention further provides a flow from each of the treatment liquid supply tanks when the treatment liquid is switched and supplied from each of the treatment liquid supply tanks to the plurality of cell trapping devices. A switching means for selectively connecting at least one of a channel and a flow channel for guiding and supplying the treatment liquid to each one of the plurality of cell capture devices according to the treatment. The cell capture processing system according to any one of [1] to [4], which is characterized by the above.
[6] In the present invention, the switching means includes at least one process selected from the group consisting of a washing process, a replacement process, an immobilization process (preservation process), a permeation process, and a staining process. The cell capture treatment system according to [5], wherein the treatment liquid supply method is controlled so as not to overlap each other.
[7] The present invention relates to the cell capture processing system according to [5] or [6], wherein the switching unit is individually provided in each of the plurality of cell capture devices.
[8] The present invention relates to the cell capture processing system according to any one of [1] to [7], wherein the cell capture device is a circulating tumor cell (CTC) capture device.
[9] In the present invention, the cell trapping device is introduced from each one of a cell trapping device incorporating a cell trapping filter, a test liquid supply container as the sample, and the treatment liquid supply tank. The cell capture treatment system according to any one of [4] to [8], wherein the cell capture treatment system includes an induction flow path for inducing and supplying a treatment liquid.
[10] The present invention is for incorporating a processing solution used in the cell capture processing system according to any one of [1] to [9] as a part of the apparatus so that the plurality of the cell capture apparatuses can share the processing solution. In the treatment liquid supply kit, the cells present in the biological sample are subjected to at least one treatment selected from a washing treatment, a replacement treatment, an immobilization treatment (preservation treatment), a permeation treatment, and a staining treatment. Each one of the treatment liquid supply tanks each holding a different type of treatment liquid depending on the content of the treatment, and the treatment liquid is supplied from each one of the treatment liquid supply tanks to the plurality of cell capture devices, respectively. The present invention relates to a treatment liquid supply kit having a plurality of the flow paths for the purpose.

  According to the present invention, the necessary processing to be performed when operating a plurality of cell capture devices used to sort and concentrate cells of a predetermined size in a biological sample by filtration, Since various processes including washing, immobilization, permeation, and staining can be shortened and simplified, multiple specimens can be processed efficiently and in a short time. It becomes. Furthermore, the entire cell capture processing system having the cell capture device can be made compact and maintenance can be simplified, and costs for capturing and analyzing cells can be reduced.

  Further, according to the treatment liquid supply kit of the present invention, the incorporation into the cell capture processing system of the present invention can be easily performed only by connecting the flow path provided in the treatment liquid supply kit and one part of the cell capture device. be able to. Furthermore, since the treatment liquid supply tank can be easily replaced, maintenance for repairing or cleaning the cell capture processing system can be simplified.

It is a figure which shows the cell capture processing system by the 1st Embodiment of this invention. It is a figure which shows an example of the process of a circulating tumor cell (CTC) implemented in a cell capture device. It is a figure which shows the conventional cell capture processing system which has one of the cell capture apparatuses. It is a figure which shows the cell capture processing system by the 2nd Embodiment of this invention. It is a figure which shows an example of the cell capture processing system by the 3rd Embodiment of this invention. It is a figure which shows another example of the cell capture processing system by the 3rd Embodiment of this invention. It is a figure which shows an example of the cell capture processing system by the 4th Embodiment of this invention. It is a figure which shows another example of the cell capture processing system by the 4th Embodiment of this invention. It is a figure which shows the cell capture processing system by the 5th Embodiment of this invention. It is a front view which shows arrangement | positioning of each apparatus which comprises the cell capture processing system by the 1st Embodiment of this invention, and an enlarged view which shows the right side surface of the apparatus containing a process liquid supply kit.

  Hereinafter, an embodiment of a cell capture processing system according to the present invention will be described with reference to the drawings.

<First Embodiment>
FIG. 1 is a schematic diagram showing a cell capture processing system according to a first embodiment of the present invention. The cell capture processing system 1 shown in FIG. 1 includes two cell capture devices 2 (Ch1 and Ch2) for selecting and concentrating circulating tumor cells (CTC) contained in blood, and the circulating tumor cells. Each of the processing liquid supply tanks 3 (A to H) respectively holding different types of processing liquids according to the processing, and the processing liquid supply tanks A to H Each treatment liquid held in each one of H is configured to be shared between the two cell capture devices 2.

  Each processing liquid held in the processing liquid supply tank 3 is supplied by a switching operation to each of the cell trapping apparatuses 2. For example, as shown in FIG. 1, the switching operation can be performed by selectively connecting the flow path of the processing liquid by the switching unit 4. The switching means 4 is connected to the flow path 5 from the processing liquid supply unit on the inlet side, and to the flow path 6 for guiding the processing liquid to the cell trapping device 7 on the outlet side. Here, as the switching means 4, it is practical to use a switching valve or the like because the flow path can be easily selected.

  The cell trapping device 2 surrounded by a one-dot chain line in FIG. 1 is at least a cell trapping device (sometimes referred to as a filter unit) containing a cell trapping filter having size selectivity in order to trap cells by filtration. ) 7 and a flow path connecting the blood collection tube for supplying blood corresponding to the sample supply container 8 serving as the specimen, and the cell collection device 7 and the blood collection tube serving as the sample supply container 8 9.

  The two cell trapping apparatuses 2 shown in FIG. 1 are connected to an external pump 11 for supplying and discharging blood through the flow path 10. Here, as the pump 11, for example, a peristatic pump can be used. The blood after cell capture is completed is discharged from the pump 11 to the waste liquid tank 13 through the flow path 12. Although not shown in FIG. 1, the flow path 5, the flow path 6, and the flow paths 9, 10, and 12 have one or two valves for adjusting blood supply and discharge as necessary. More than one place is provided.

  FIG. 1 shows a cell capture processing system in which the waste liquid tank 13 is shared between the two cell capture devices 2, but one waste liquid tank 13 is provided for each cell capture device 2. A system that does not share the cell capture devices 2 may be adopted. The method of sharing the waste liquid tank 13 has the advantage that not only the installation space can be reduced and the equipment cost can be reduced, but also the storage and processing of the waste liquid can be integrated and managed including the waste liquid analysis. Therefore, it is suitable in the present invention.

  In addition to the cell trapping filter, the cell trapping device 7 shown in FIG. 1 includes an upper member, a sealing material, a lower member, and the like, and the number and structure of the cell trapping filters can be changed as necessary. Here, the cell trapping device 2 may be referred to as a filter cell unit, and is detachable so that it can be freely attached to and detached from the cell trapping processing system of this embodiment.

  Each of the treatment liquid supply tanks 3 composed of A to H shown in FIG. 1 supplies different types of treatment liquids according to various kinds of treatments performed when the circulating tumor cells (CTC) are selected and concentrated in the cell capture device 2. Each is held separately. FIG. 2 shows an example of processing steps when circulating tumor cells (CTC) are selected and concentrated in the cell capture device 2. The processing steps shown in FIG. 2 are not defined as processing steps for circulating tumor cells (CTC), and some of the steps are omitted or other steps are added as necessary.

  As shown in FIG. 2, after the blood sample is filtered in the step S1 with the filter cell portion attached, the circulating tumor cells (CTC) are largely processed in three steps. First, in order to carry out the antiseptic treatment of the cells, the treatment step consisting of S2, S3 and S4 for washing, immobilization and standing, and then washing, permeation and standing for carrying out the cell drilling treatment S5 , S6 and S7, and further processing steps consisting of S8, S9, S10 and S11 for washing, staining, standing and washing in order to stain cells. Finally, the filter cell part is removed and circulating tumor cells (CTC) are detected and analyzed.

  In FIG. 2, the cleaning process performed in steps S2, S5, S8, and S11 is often performed using the same type of processing liquid. The cleaning process is performed using at least one of the cleaning liquid, the buffer solution, and the rinsing liquid. However, the cleaning process may be performed by continuously supplying two or more processing liquids as necessary. Good. Further, the order in which two or more types of supply liquids, that is, a cleaning liquid, a buffer solution, and a rinsing liquid, are supplied can be changed according to the cleaning processing method. For example, when processing is performed in this order using a cleaning solution, a buffer solution, and a rinsing solution, three types of processing solutions are individually prepared and cleaning processing is performed. The washing solution, the buffer solution and the rinsing solution are usually used in a phosphoric acid aqueous solution, and are used separately when the phosphoric acid concentration of the aqueous solution or the types and concentrations of other additives are different. In addition, when the composition and type of the processing liquid are the same, one type of processing liquid is used as the same type of cleaning liquid.

  The immobilization treatment step S3 is performed in order to prevent the state of circulating tumor cells (CTC) in the blood sample captured by the filtration step S1 from oxidative deterioration or property change over time. As the treatment liquid, for example, a fixing liquid made of an aqueous solution containing paraformaldehyde having a high corrosion prevention effect is used.

  The staining process step S9 is a process performed to identify circulating tumor cells (CTC). For example, this process is used when counting circulating tumor cells (CTC) using a fluorescence microscope. Perform fluorescent immunostaining. Circulating tumor cells (CTC) may use different staining solutions depending on the type of cell line. In this case, two or more different types of staining solutions are prepared and stained.

  In FIG. 2, after each step of the immobilization process of S3, the permeation process of S6, and the staining process of S9, in order to ensure the penetration of each processing solution into the cells, the fixing solution, permeation solution and staining are performed. A standing step is provided in which the substrate is left for a predetermined time in a state immersed in the liquid. As the standing time, 5 minutes or more is practical, but it is preferable to stand for 10 minutes or more in order to perform reliable treatment. However, if the standing time is increased, the total time required for analysis is increased, so that efficient processing cannot be performed, and further, adverse effects due to long-time immersion of each processing solution occur, and therefore preferably within 60 minutes, more preferably Is within 40 minutes.

  When the types of processing liquids required for each processing shown in FIG. 2 are different, one processing liquid supply tank is provided according to the number of types. The processing liquid supply tank 3 shown in FIG. 1 collectively shows supply tanks each holding eight types of processing liquids. In FIG. 1, the treatment liquid supply tanks A to C each have three types of staining liquids having different compositions. The treatment liquid supply tanks D, E, F, G, and H are tanks that hold different types of buffer solution, rinse solution, cleaning solution, fixing solution, and permeate solution, respectively. Here, the number of treatment liquid supply tanks A to C that hold the staining liquid is not limited to three. It suffices to prepare as many types of staining solutions as necessary. Further, the treatment liquid supply tanks D to F show examples in which the types are different in the cleaning liquid, the buffer liquid, and the rinsing liquid used in the cleaning process. When at least two types are the same in each processing liquid, the number of processing liquid supply tanks may be reduced depending on the type.

  In the cell trapping device, after the washing step, a replacement treatment step for replacing cells with a liquid different from the washing liquid may be introduced. This replacement treatment is rarely used for the purpose of concentrating and recovering circulating tumor cells (CTC), but is introduced in a cell analyzer used to sort different types of cells by a predetermined size. May be. Therefore, the process performed in the cell capture processing system of the present embodiment includes at least one process selected from the group consisting of a cleaning process, a replacement process, an immobilization process (preservation process), a permeation process, and a staining process. The configuration of the processing liquid supply tank 3 can be determined according to one or more processing operations performed depending on the application.

  When a blood sample is processed for the concentration and collection of circulating tumor cells (CTC) according to the process example shown in FIG. 2, the time required for the steps S1 to S11 is usually 100 minutes or more including the stationary processing time. It may take such a case. As shown in FIG. 3, in the case where the steps S1 to S11 are performed independently by a conventional cell capture processing system having one cell capture device 2, from A to H in addition to a processing time of 100 minutes or more. The time required for the replacement of each processing solution held in the processing solution supply tank and the removal and attachment of each pipe and the adjustment thereof is extra as much as the number of installed cell trapping devices 2 increases. In order to shorten the adjustment time, it is possible to simultaneously replace each processing solution for two of the cell trapping apparatuses 2, but in that case, manpower and labor according to the number of installed cell trapping apparatuses 2 are required. It becomes.

  On the other hand, as shown in FIG. 1, in the cell capture processing system 1 of this embodiment, it is possible to shorten the time required for the replacement of the processing liquid and the connection and adjustment of each pipe. Although it is difficult to reduce the time required for various processes shown in FIG. 2, it is possible to reduce the time required for replacement of each processing solution and the various operations associated therewith, so that a plurality of blood samples can be efficiently analyzed simultaneously. . The method of supplying each processing solution from the processing solution supply tank 3 to the two cell capture devices 2 is programmed and controlled so that each processing solution can be automatically and selectively supplied by the switching means 4 according to the processing procedure. Can do. Thereby, not only the supply of each processing solution between the plurality of cell capture devices 2 is performed smoothly, but also the trouble of removing and installing the piping and adjusting the connection of the piping that are usually performed in association with the replacement of the processing solution. Can be saved. Furthermore, the cell capture processing system 1 of the present invention shown in FIG. 1 has the number and the number of processing liquid supply tanks 3 holding each processing liquid, as compared with the case where two conventional ones are juxtaposed as shown in FIG. Since the space can be reduced, the apparatus can be made compact and the equipment cost can be reduced. Further, minimizing the number of processing liquid supply tanks 3 that hold each processing liquid contributes to simplification of maintenance and reduction of maintenance costs.

  In the cell capture processing system 1 of the present embodiment, when concentration and collection of circulating tumor cells (CTC) are performed using two of the cell capture devices 2, the analysis results of both devices do not vary. There is a need to. Therefore, the flow rate or flow rate of each treatment liquid when supplying each of the treatment liquid supply tanks 3 to each of the plurality of cell capture devices 2 is substantially equal among the plurality of cell capture devices 2. At least one of the length and diameter of the flow path 6 for guiding and supplying each processing liquid, the flow rate of each processing liquid, and the positional relationship when the processing liquid supply tank 3 and the plurality of cell trapping devices 2 are arranged. It is preferable to adjust this.

As shown in FIG. 1, the flow rate or flow rate of each treatment liquid when supplying each of the treatment liquid supply tanks 3 to each of the plurality of cell capture devices 2 is, for example, in the middle of the flow path 6 in the flow path. It is possible to measure by providing a liquid flow detection unit 14 that detects and measures a change in flow rate of each of the treatment liquids. The signal detected by the liquid flow detection unit 14 is supplied to the CPU 18 via the controller 16 and the interface 17 provided in the arithmetic processing unit 15, and is converted into the discharge liquid amount of each processing liquid. The CPU 18 compares the discharge liquid amount obtained by converting the detection signal with a predetermined liquid amount set value, and compares whether the discharge liquid amount is different between the two cell trapping devices 2. To do. If the discharged liquid amount is out of the allowable range of the set value or a difference is detected between the two cell trapping devices 2, the two pumps are connected via the driver 19 provided in the arithmetic processing unit 15. Each of the treatments supplied to each of the cell trapping devices 2 so that the flow rate or flow rate of each of the treatment liquids is substantially equal among the plurality of cell trapping devices 2 by individually controlling each of the correction operations. Adjust the liquid flow rate.
Although FIG. 1 shows the case where the liquid flow detection unit 14 is provided in the middle of the flow path 6, it may be provided in the middle of the flow path 10, and in this case, the same function as described above can be achieved.

  As a result of monitoring by the CPU 18, when each of the two pumps 11 is individually subjected to correction operation control in accordance with fluctuations in the flow rate or flow rate of each processing solution to be supplied, such information is stored in each cell trapping device 2. It is stored or stored as reference data used for control. In addition, when it becomes difficult to control the flow rate or flow rate of the processing liquid and an abnormality occurs, an abnormality occurrence message is generated.

  The information data regarding the flow rate or flow velocity and their fluctuations, the abnormal message, and the like are displayed on the screen of the display 20 attached to the arithmetic processing unit 15 or printed out from the printer 21. If it is determined that it is difficult to continue the operation of the cell capture processing system 1 due to the occurrence of an abnormality, the CPU 18 may stop the operation of the pump 11 as necessary. Furthermore, the information data relating to the flow rate or flow velocity and their fluctuations are accumulated for the number of actual analysis operations performed, and the analysis data is analyzed by analyzing the supply status of each processing solution from the accumulated data. It can be used for smooth operation of the cell capture processing system of the present invention.

  In the cell capture processing system 1 shown in FIG. 1, in the case where the flow rate or flow rate of each treatment liquid is the same when supplying the treatment liquid between the two cell capture devices 2, The diameter and length should be the same. This is because the operation of the cell capture processing system 1 can be further simplified by setting the control conditions of the pump 11 to be the same between the two cell capture devices 2. Moreover, when the lengths of the flow paths 6 are different from each other, the lengths of the flow paths are made substantially the same between the two apparatuses by changing the positions where the two cell capture devices 2 are installed. .

  If the diameter or length of the flow path 6 is not the same between the two cell trapping devices 2, the two pumps 11 can be operated under optimum conditions by controlling the two pumps 11 individually, and 2 The flow rate or flow rate of each treatment solution can be made substantially equal between the cell capture devices 2 of the stage.

  As described above, when the cell capture processing system 1 of the present embodiment performs concentration and collection of circulating tumor cells (CTC) using two of the cell capture devices 2, the length and diameter of the flow path 6, By adjusting at least one of the flow rate of each processing solution and the positional relationship when the processing solution supply tank 3 and the plurality of cell trapping devices 2 are arranged, one to two of the processing solution supply tanks 3 are adjusted. The flow rate or flow rate of each processing solution when supplied to the cell capture device 2 can be made substantially equal between the two devices. In the present embodiment, the cell capture processing system 1 shown in FIG. 1 having two cell capture devices 2 has been described. However, even the cell capture processing system 1 having three or more cell capture devices 2 is the same as described above. The method is employed to prevent variation in analysis among the plurality of cell capture devices 2.

  Furthermore, in the cell capture processing system 1 of the present embodiment, the biological sample processed by one of the cell capture devices 2 is treated with different types of treatment liquids depending on the content of the process, with the number of cell capture devices 2 being n1. When the number of samples in the sample is m, it is more preferable that the treatment liquid supply tank 3 has a volume amount n (n = n1 × m) times or more of the volume required for one treatment of the sample. Thereby, since the amount of each processing liquid necessary for various processing is held in the processing liquid supply tank 3 for a plurality of cell trapping apparatuses 2, it is necessary to exchange each processing liquid during the processing. Not only can it be eliminated, but the frequency of replacement of each processing solution can be reduced.

  The cell capture processing system 1 shown in FIG. 1 has two cell capture devices 2. For example, the number of blood samples processed by one cell capture device 2 is 8 samples per day, and one sample of blood is collected. In the case where the amount of the processing liquid required for performing a predetermined processing is 1 ml (milliliter), the processing liquid previously held in one tank of the processing liquid supply tank 3 is at least 16 ml (milliliter). is there. For other processes, the amount of the processing liquid for performing the process is determined in the same manner. Here, if each processing liquid is stored in one of the processing liquid supply tanks 3 in an amount larger than the amount used for the operation per day, a margin is created in the holding amount. Even if some trouble occurs in the initial stage of operation or during the operation, it is not necessary to replenish each processing solution. As described above, if the holding amount of each processing liquid is estimated for each tank of the processing liquid supply tank 3, the replacement operation of each processing liquid during the operation of one day can be omitted. High efficiency can be achieved.

<Second Embodiment>
FIG. 4 is a diagram showing a cell capture processing system according to the second embodiment. The cell capture processing system 1 shown in FIG. 4 is different from the cell capture processing system shown in FIG. 1 in that one switching means 4 is provided for two cell capture devices 2 (Ch1 and Ch2).

  In the cell capture processing system 1 shown in FIG. 4, the processing liquid (A shown in FIG. 4) held in one of the processing liquid supply tanks 3 enters one inlet 31 of the switching means 4, and 2 by the switching means 4. After being divided into two passages, they are supplied to the cell trapping devices (filter units) 7 of the two cell trapping apparatuses 2 from the two outlets 41 and 42 of the switching means 4 connected to the respective flow paths 6. The Although FIG. 4 illustrates the case of A as the processing liquid, the processing liquid supplied from the processing liquid supply tank 3 through the flow path 5 to the inlet of the switching means 4 is changed according to the processing content. Thus, it is possible to simultaneously proceed with the same processing by two units of the cell trapping device 2.

  The method in which each processing solution is supplied separately to the plurality of cell trapping devices 2 by one of the switching means 4 is different from the case of FIG. 1 in which the switching means 4 is individually provided in each of the cell trapping devices 2. This reduction not only reduces the apparatus cost but also reduces the installation cost because only one switching means 4 is required to be installed and adjusted. On the other hand, since it is necessary to divide the processing liquid put in from one inlet of the switching means 4 into two flow paths, it is fine to make the supply amount of each processing liquid equal between the two cell trapping devices. Control and fine tuning are required. Therefore, it is preferable to adopt the method shown in FIG. 1 in order to prevent the analysis results from being varied between the plurality of cell capture devices 2 with high accuracy.

  However, even in a method in which each processing solution is supplied by one of the switching means 4, it is possible to reduce variations in analysis results by preventing each processing from overlapping each other among the plurality of cell capture devices 2. Is possible. This method will be described in detail in a fifth embodiment to be described later.

<Third Embodiment>
About the cell capture processing system of this embodiment which is equipped with 4 units | sets of the cell capture | acquisition apparatus 2, and uses the process liquid supply tank 3 which holds only one kind of different process liquids by 2 units | sets and 4 units | sets of cell capture units 2 respectively. These will be described with reference to FIGS. 5 and 6, respectively.

  The cell capture processing system 1 shown in FIG. 5 includes switching means 4 used for supplying each processing solution in each of the four cell capture devices 2. The treatment liquid supply tank 3 can perform processing operations of the four cell capture devices 2 (Ch1, Ch2, Ch3, and Ch4) simultaneously by providing two sets shared by the two cell capture devices 2. it can. FIG. 5 shows an example having two sets of treatment liquid supply tanks 3, but only one set of the treatment liquid supply tanks 3 for simultaneously performing the processing operations of the four cell capture devices 2. It may be.

  The cell capture processing system 1 shown in FIG. 6 uses one set of the treatment liquid supply tank 3 to perform processing operations of the four cell capture devices 2 (Ch1, Ch2, Ch3, and Ch4) at the same time. In this example, each processing solution is supplied to each cell trapping device 2 by the switching means 4. In this example, the processing operation of the four cell capture devices 2 is performed by one set of the treatment liquid supply tank 3 and one of the switching means 4. The processing steps between the four cell capture devices 2 may be simultaneous or different.

  5 and FIG. 6, in order to substantially equalize the flow rate or flow rate of each processing solution among the four cell capture devices 2, as in the case shown in FIG. A liquid flow detector 14 (not shown) that detects and measures changes in the flow velocity of each processing liquid in the flow path is provided in the middle of the channel 10, and a method of individually correcting and controlling the operation of the pump 11 for each pump 11 is adopted. May be. In addition, regarding the arrangement of the treatment liquid supply tank 3 or the diameter and length of the flow path 6 when the treatment liquid is supplied, the flow rate or flow rate of each treatment liquid is substantially equal among the four cell capture devices 2. To be equal to.

  Furthermore, in order not only to eliminate the need to replace each processing solution in the middle of processing, but also to reduce the replacement frequency of each processing solution, different types of processing solutions are used according to the contents of the processing. When the number of specimens in the biological sample to be processed by the table is m specimens, the treatment liquid supply tank 3 has a volume amount n (n = 4 × m) or more of the volume required for one treatment of the specimen. It is preferable to make it.

  The cell capture processing system 1 of this embodiment does not need to limit the number of the cell capture devices 2 to two or four, and two or more cell capture devices 2 are required from the viewpoint of installation space of the device, maintenance labor, analysis cost, and the like. An appropriate number can be selected and provided.

<Fourth Embodiment>
As described above, the cell capture processing system 1 of the present embodiment includes the processing in at least one processing selected from the group consisting of washing processing, replacement processing, immobilization processing (preservation processing), permeation processing, and staining processing. May be controlled by the switching means (switching valve) 4 so that the processing liquid supply method does not overlap each other among the plurality of cell capture devices 2.

  7 and 8 show the cell capture processing system 1 of the present embodiment in which various processes are controlled by the switching unit 4 so that they do not overlap each other between the two cell capture devices 2. Here, FIG. 7 shows an example in which two switching means 4 are attached to the two cell trapping apparatuses 2 and each processing solution is supplied to the respective cell trapping apparatuses 2 by the respective switching means 4. is there. Further, FIG. 8 is an example in which means for supplying each processing solution to each cell trapping apparatus 2 is performed by one switching means 4 in order to perform processing operations of two cell trapping apparatuses 2 simultaneously.

  In the cell capture processing system 1 shown in FIG. 7, the processing liquid (A shown in FIG. 7) held in one of the processing liquid supply tanks 3 enters one inlet 31 of the switching means 4 located on the left side of the figure. From the outlet 41, it is supplied to the cell trapping device (filter unit) 7 of the cell trapping apparatus 2 located on the left side of the figure. On the other hand, another processing liquid (F shown in FIG. 7) enters another inlet 32 of the switching means 4 located on the right side of the figure, and from the outlet 41 the cell trapping device ( Filter unit) 7.

  Further, in the cell capture processing system 1 shown in FIG. 8, the processing liquid (A shown in FIG. 8) held in one of the processing liquid supply tanks 3 is one inlet 31 of the switching means 4 located in the center of the figure. And is supplied from the outlet 41 to the cell trapping device (filter unit) 7 of the cell trapping apparatus 2 located on the left side of the figure, and another processing liquid (F shown in FIG. 8) is supplied to another inlet of the same switching means 4. 32 and supplied from another outlet 42 to the cell trapping device (filter unit) 7 of the cell trapping apparatus 2 located on the right side of the figure.

  7 and 8 exemplify cases of A and F as processing liquids, the types of processing liquids in the processing liquid supply tank 3 and the inlets and outlets of the switching means 4 connected to the processing liquids are used as processing contents. By changing accordingly, it is possible to simultaneously proceed with different contents for the two cell capture devices 2.

  In this way, by controlling the supply method of each treatment liquid by the switching means 4 so that various treatments do not overlap each other between the two cell trapping devices 2, the supply amount of each treatment liquid is reduced to two. Fine control and fine adjustment of the pump 11 are reduced in order to make it uniform between the cell trapping devices 2. Thereby, not only can labor for adjusting analysis conditions be saved, but also the effects of preventing troubles during analysis and reducing variations in analysis results can be obtained. In particular, the cell capture processing system 1 shown in FIG. 8 not only stably obtains the same analysis result between the two cell capture devices 2, but also has only one switching means 4, so The reduction can simultaneously reduce the apparatus cost and the cost for its installation and maintenance.

<Fifth Embodiment>
FIG. 9 is a diagram showing a cell capture processing system of the present embodiment in which four cell capturing devices 2 are provided and the supply of each processing solution from the processing solution supply tank 3 is controlled by one of the switching means 4. The cell trapping processing system 1 shown in FIG. 9 has basically the same function as the cell trapping processing system 1 shown in FIG. 8 except that the number of the cell trapping devices 2 provided is different.

  In FIG. 9, each of the processing liquids A, F, G, and H held in one of the processing liquid supply tanks 3 enters one inlet 31, 32, 33, and 34 of the switching unit 4 and exits 41, 42. , 43 and 44 are supplied to the cell trapping devices (filter units) 7 of the respective cell trapping apparatuses 2 positioned in order from the left side of the figure. As in the case of FIG. 1, each processing solution is supplied to each cell trapping device 2 in an arithmetic processing unit (not shown) by performing various processes by programming according to a preset switching procedure. The cell trapping devices 2 can be controlled so as not to overlap each other. Further, when the number of specimens in a biological sample processed by one of the cell capture devices 2 is set to m specimens depending on the type of treatment, the volume required for one treatment of the specimen is increased. By holding the volume amount of n (n = 4 × m) times or more in the processing liquid supply tank 3, not only does it become unnecessary to replace each processing liquid in the middle of the processing, but also the replacement frequency of each processing liquid is increased. Can be reduced.

  As described above, the cell capture processing system 1 shown in FIG. 9 can double the number of samples to be processed in the same processing time as compared with that shown in FIG. Furthermore, it is not necessary to exchange each processing solution in the processing solution supply tank 3 during a predetermined analysis time. Therefore, it is possible to further reduce the labor and time for replacement.

<Sixth Embodiment>
A treatment liquid supply kit for incorporation into the cell capture treatment system of the present embodiment will be described with reference to FIG. In FIG. 10, (a) is a front view showing the arrangement of each device constituting the cell capturing processing system according to the first embodiment of the present invention, and (b) is a processing liquid supply incorporated in the cell capturing processing system. It is an enlarged view which extracts only the apparatus containing a kit and shows the right side.

  In the cell capture processing system 1 shown in FIG. 10 (a), two cell capture devices 2 are disposed on the left and right sides of the upper stage, and a treatment liquid supply tank 3 is disposed on the mount 51 in the center. Two pumps 11 are disposed on both the left and right sides of the pump, and a waste liquid tank 13 is disposed on the gantry 52 at the center. A switching means 4 is installed in the upper part of the processing liquid supply tank 3, and the switching means 4 is connected to the flow path 5 piped to each one (A to H) of the processing liquid supply tank 3. Furthermore, a flow path 6 for guiding each processing solution from the switching means 4 and guiding it to the cell trapping device 2 is provided. A liquid flow detection unit 14 is provided in the middle of each flow path 6, and a signal detected by the liquid flow detection unit 14 is supplied to an arithmetic processing unit 15 having a controller, an interface, a CPU, and a driver (not shown). Is done. Moreover, the flow path 10 for guiding the waste liquid after each treatment to the pump 11 from each of the two cell trapping devices 2 arranged in the upper stage passes from the upper part to the lower part. Further, the pump 11 is connected to the waste liquid tank 13 through the flow path 12. Inside each of the two cell trapping apparatuses 2, a flow path 9 (not shown) that connects the cell trapping device 7 and the blood supply container is provided.

  In the present invention, as shown in FIG. 10A, at least one of the two cell trapping devices 2 is in operation with the warning lamp 53 installed at the top of the cell trapping processing system 1. May be displayed. Accordingly, it is possible to visually confirm whether or not the analysis is in progress, so that the cell capture processing system 1 can be easily managed.

  FIG. 10 (b) shows the right side of the apparatus comprising the switching means and the treatment liquid supply kit incorporated in the cell capture treatment system 1, and the portion surrounded by the alternate long and short dash line is in the treatment liquid supply kit 50. The corresponding part. (B) of FIG. 10 illustrates the treatment liquid supply kit 50 used for selecting and concentrating circulating tumor cells (CTC) contained in blood, and includes washing treatment, washing treatment, and immobilization treatment. (Preservation treatment), at least one treatment of a group selected from a permeation treatment and a dyeing treatment is performed. The processing liquid supply kit 50 includes each one of the processing liquid supply tanks 3 each holding different types of processing liquids A to G depending on the contents of the processing, and each of the processing liquids in each of the processing liquid supply tanks 3. And eight of the flow paths 5 for supplying the switching means 4 from one to the other.

  The treatment liquid supply kit 50 is detachable by attachment and detachment so that it can be incorporated into the cell capture treatment system 1 shown in FIG. Thereby, the cell capture processing system 1 attaches the treatment liquid supply kit 50 before starting the operation, and removes it after the analysis is completed and the operation is completed. If a problem occurs in the processing liquid supply kit 50, the analysis operation is performed by attaching the other processing liquid supply kit 50 to the cell capture processing system 1 while removing it and performing cleaning and maintenance separately. Can continue. Thus, the processing liquid supply kit 50 of this embodiment can be used as a user-friendly component.

  Replenishment of the processing liquid to the processing liquid supply kit 50 is performed when the processing liquid supply kit 50 is removed. As described in the first embodiment, the amount of each treatment liquid is two cell capture devices 2, and the number of samples in a biological sample processed by one cell capture device 2 is m samples. In this case, each of the treatment liquid supply tanks 3 holds a volume amount of n (n = 2 × m) times or more of the volume necessary for one treatment of the specimen, so that various treatments can be performed. Thus, it is not only necessary to replace each processing solution, but also the replacement frequency of each processing solution can be reduced.

  In the present embodiment, an example of the cell trapping processing system 1 including two cell trapping devices 2 and eight types of processing liquids has been shown. However, the size and shape of the processing liquid supply tank 3 and the processing liquid supply tank 3 The volume of each processing solution held in each one can be changed according to the number of cell trapping devices 2 and the number of processing solutions. In addition, the treatment liquid supply kit 50 of this embodiment is used not only for analysis of circulating tumor cells (CTC) shown in FIG. 10, but also for cell analysis apparatus for separating red blood cells, white blood cells, bacteria, etc. present in a biological sample. In the case of application to the above, as a treatment liquid held in one of the treatment liquid supply tanks 3, a replacement treatment liquid required for a treatment performed by the cell analyzer, for example, a substitution treatment may be prepared.

  As described above, according to the present invention, necessary processing performed when operating a plurality of cell capture devices used for sorting and concentrating by filtration, that is, washing, replacement, staining, etc. Thus, it is possible to reduce the time and the labor for various processes including the above, and to process a plurality of specimens efficiently and in a short time. Furthermore, the entire cell capture processing system having the cell capture device can be made compact and maintenance can be simplified, and costs for capturing and analyzing cells can be reduced.

  Further, by incorporating a removable processing liquid supply kit into the cell capture processing system of the present invention, the processing liquid supply tank can be easily replaced. By using the treatment liquid supply kit of the present invention, it is possible to simplify maintenance for repair or cleaning, etc., and to have an advantage that analysis operation by the cell capture processing system can be continued even in a situation where a failure occurs. Its usefulness is extremely high.

DESCRIPTION OF SYMBOLS 1 ... Cell capture processing system 2 ... Cell capture apparatus 3 ... Processing liquid supply tank 4 ... Switching means 5, 6, 9, 10, 12 ... Channel 7 ... Cell capture device 8 ... Supply container for test liquid 11 ... Pump 13 ... Waste liquid tank 14 ... Liquid flow detector 15 ... Arithmetic processor 16 ... Controller 17 ... Interface 18 ... CPU
DESCRIPTION OF SYMBOLS 19 ... Driver 20 ... Display 21 ... Printer 31, 32, 33, 34 ... Entrance of switching means 41, 42, 43, 44 ... Exit of switching means 50 ... Supply of processing liquid Kit 51, 52 ... Base 53 ... Warning light

Claims (10)

A cell capture processing system having a cell capture device for sorting and concentrating cells of a predetermined size in a biological sample by filtration,
A plurality of the cell trapping equipment,
The cells present in the biological sample are subjected to at least one treatment selected from the group consisting of a washing treatment, a substitution treatment, an immobilization treatment (preservation treatment), a permeation treatment, and a staining treatment. One or more treatment liquid supply tanks each holding a treatment liquid,
The treatment liquid held in one or more treatment liquid supply tanks is shared among a plurality of the cell capture devices,
A plurality of pumps connected to each of the plurality of cell trapping devices and controlling the flow rate of the treatment liquid supplied to the cell trapping device;
A plurality of liquid flows that are provided for each of the plurality of cell trapping devices and detect and measure changes in the flow rate of the processing liquid supplied to each of the plurality of cell trapping apparatuses from one or more of the processing liquid supply tanks. A detection unit;
Based on the results of detection measurement by the plurality of liquid flow detection units, the plurality of pumps are controlled so that the flow rate or flow rate of the treatment liquid is substantially equal among the plurality of cell trapping devices. An arithmetic processing unit that adjusts the flow rate of the processing solution supplied to each of the plurality of cell trapping devices;
Cell capture processing system characterized by having a.   2. The cell capture processing system according to claim 1, further comprising a single waste liquid tank for storing a waste liquid, wherein the waste liquid tank is shared between the plurality of cell capture devices. The treatment liquid is adjusted so that the flow rate or flow velocity when supplying the treatment liquid from one or more treatment liquid supply tanks to the plurality of cell capture devices is substantially equal among the plurality of cell capture devices. the length and diameter of the channel for supplying induction to, claims and adjusting at least one of the positional relationship when placing 及 beauty treatment fluid supply tank and a plurality of said cell capture device Item 3. The cell capture processing system according to Item 1 or 2.   Different types of treatment liquids depending on the content of the treatment, when the number of cell capture devices is n1, and the number of samples in the biological sample processed by one of the cell capture devices is m samples, 4. The process liquid supply tank has a volume amount of n (n = n1 × m) times or more of a volume required for one process of the specimen, according to claim 1. Cell capture processing system. Furthermore, when the processing liquid is switched and supplied from one or more of the processing liquid supply tanks to the plurality of cell trapping apparatuses, the flow path from the one or more of the processing liquid supply tanks and the plurality of the cell trapping apparatuses 5. A switching means for selectively connecting at least one of the flow paths for inducing and supplying the processing liquid to each one according to the processing. The cell capture processing system according to any one of the above.   By the switching means, in at least one process selected from the group consisting of a cleaning process, a replacement process, an immobilization process (preservation process), a permeation process, and a staining process, the processes overlap each other among the plurality of cell trapping devices. The cell capture processing system according to claim 5, wherein a supply method of the processing liquid is controlled so as not to cause a failure.   The cell capture processing system according to claim 5 or 6, wherein the switching unit is individually provided in each of the plurality of cell capture devices.   The cell capture processing system according to any one of claims 1 to 7, wherein the cell capture device is a circulating tumor cell (CTC) capture device. The cell trapping device induces and supplies a cell trapping device incorporating a cell trapping filter, a supply container for a test liquid which is the biological sample , and the treatment liquid introduced from one or more treatment liquid supply tanks The cell capture processing system according to claim 8, wherein the cell capture processing system is a device having a flow path for performing the operation. A treatment liquid supply kit for incorporating the treatment liquid used in the cell capture treatment system according to any one of claims 1 to 9 as a part of the apparatus so that the plurality of cell capture apparatuses can share the treatment liquid. The cells present in the biological sample are subjected to at least one treatment selected from the group consisting of a washing treatment, a substitution treatment, an immobilization treatment (preservation treatment), a permeation treatment, and a staining treatment. 1 and above of the treatment liquid supply tank held type of processing liquid, respectively, and a plurality of flow paths for supplying respectively said treatment liquid from one or more of the treatment liquid supply tank to a plurality of the cell capturing apparatus A processing solution supply kit.

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